The interface between glucocorticoid signaling and histone acetylation in erythropoiesis

PROJECT SUMMARY/ABSTRACT Chronic glucocorticoid therapy is a mainstay of treatment for Diamond-Blackfan anemia (DBA), but leads to a number of toxicities including, but not limited to, gastric ulcers, immunosuppression, hyperglycemia, renal dysfunction, steatosis, adrenal suppression, hypertension, osteoporosis, and cataracts. These toxicities are severe enough that nearly half of DBA patients must discontinue glucocorticoid therapy. Alternatives to glucocorticoids include chronic red cell transfusions and hematopoietic stem cell transplantation, but chronic transfusions are associated with a number of toxicities from iron overload and alloimmunization, and stem cell transplantation carries risks of mortality from conditioning toxicity and graft versus host disease. Thus, new approaches for reducing toxicity when treating DBA are required. Over the course of our prior research funded by the K08 awarded to the principal investigator, we identified inhibition of histone acetyltransferase (HAT) activity as an intervention that increases the number of erythroblasts produced by an individual early erythroid progenitor cell. Furthermore, HAT inhibition also synergized with glucocorticoids to increase erythroblast production by over an order of magnitude. The goal of this proposal will be to advance a new research focus assessing the interplay between glucocorticoid signaling and HAT regulation of erythropoiesis. The genesis of this line of investigation arose from follow-up experiments to the principal investigator’s K08, but have diverged from the K08 aims of identifying specific gene targets of glucocorticoid receptor and instead focus on glucocorticoid interactions with epigenetic regulators. We will (i) determine if glucocorticoid receptor directly interacts or colocalizes with HATs, and (ii) determine if HAT inhibition phenocopies glucocorticoid-induced slowing of erythroid differentiation as a mechanism for increasing erythroid progenitor cell proliferative capacity. Through these efforts, we will generate data that informs strategies for preclinical development of HAT inhibition for DBA, and expand the repertoire of the principal investigator’s research program.